Neuropharmacology
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Comparative Study
The preferential mGlu2/3 receptor antagonist, LY341495, reduces the frequency of spike-wave discharges in the WAG/Rij rat model of absence epilepsy.
We examined the expression and function of group-II metabotropic glutamate (mGlu) receptors in an animal model of absence seizures using genetically epileptic WAG/Rij rats, which develop spontaneous non-convulsive seizures after 2-3 months of age. Six-month-old WAG/Rij rats showed an increased expression of mGlu2/3 receptors in the ventrolateral regions of the somatosensory cortex, ventrobasal thalamic nuclei, and hippocampus, but not in the reticular thalamic nucleus and in the corpus striatum, as assessed by immunohistochemistry and Western blotting. In contrast, mGlu2/3 receptor signalling was reduced in slices prepared from the somatosensory cortex of 6-month-old WAG/Rij rats, as assessed by the ability of the agonist, LY379268, to inhibit forskolin-stimulated cAMP formation. ⋯ To examine whether pharmacological activation or inhibition of mGlu2/3 receptors affects absence seizures, we recorded spontaneous spike-wave discharges (SWDs) in 6-month-old WAG/Rij rats systemically injected with saline, the mGlu2/3 receptor agonist LY379268 (0.33 or 1 mg/kg, i.p.), or with the preferential mGlu2/3 receptor antagonist, LY341495 (0.33, 1 or 5 mg/kg, i.p.). Injection of 1mg/kg of LY379268 (1 mg/kg, i.p.) increased the number of SWDs during 3-7 h post-treatment, whereas injection with LY341495 reduced the number of seizures in a dose-dependent manner. It can be concluded that mGlu2/3 receptors are involved in the generation of SWDs and that an upregulation of these receptors in the somatosensory cortex might be involved in the pathogenesis of absence epilepsy.
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Group II (mGluR2/3) metabotropic glutamate receptors have been implicated in the mechanisms of persistent pain states. In the present study, the effects of the selective group II metabotropic glutamate receptor agonists LY379268 and LY389795 were evaluated in the formalin test, carrageenan-induced thermal hyperalgesia and mechanical allodynia, and capsaicin-induced mechanical allodynia in rats. The agonists LY379268 and LY389795 produced dose-dependent decreases in formalin-induced behaviors that were antagonized by the mGlu2/3 receptor antagonist LY341495. ⋯ However, both agonists produced motor impairment on the inverted screen at doses that were analgesic. Moreover, tolerance to the analgesic effects of LY379268 developed after 4 days of once-daily repeated administration in the formalin, carrageenan, capsaicin and hot plate tests. The present findings indicate that group II (mGluR2/3) metabotropic glutamate receptors may be involved in the mechanisms of hyperalgesia and allodynia, however tolerance rapidly develops to these effects.
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Comparative Study
RGS-Rz and RGS9-2 proteins control mu-opioid receptor desensitisation in CNS: the role of activated Galphaz subunits.
Two consecutive i.c.v. administrations of analgesic doses of mu-opioid receptor agonists lead to a profound desensitisation of the latter receptors; a third dose produced less than 20% of the effect obtained with the first administration. Desensitisation was still effective 24h later. Impairing the activity of Galphaz but not Galphai2 subunits prevented tolerance developing after the administration of three consecutive doses of morphine. ⋯ However, impairing their activity also accelerated tachyphylaxis following successive doses of morphine, and facilitated the development of acute morphine tolerance. In contrast, inhibiting the RGS9-2 proteins, which bind to GalphaoGTP and GalphaiGTP but only weakly deactivates them, preserved the effects of consecutive morphine doses and abolished the generation of acute tolerance. Therefore, desensitisation of mu-opioid receptors can be achieved by reducing the responsiveness of post-receptor elements (via the possible action of activated Galphaz subunits) and/or by depleting the pool of receptor-regulated G proteins that agonists need to propagate their effects, e.g., through the activity of RGS9-2 proteins.